Motor and sensory impairment in survivors of childhood central nervous system (CNS) tumors in the St. Jude Lifetime Cohort (SJLIFE)

Abstract Background Survivors of childhood central nervous system (CNS) tumors can develop motor and sensory impairment from their cancer and treatment history. We estimated the prevalence of motor and sensory impairment in survivors compared with controls through clinical assessment and identified associated treatment exposures and functional, quality of life (QOL), and social outcomes. Methods Survivors of childhood CNS tumors from the St. Jude Lifetime Cohort (n = 378, median [range] age 24.0 [18.0–53.0] years, 43.4% female) ≥5 years from diagnosis and controls (n = 445, median [range] age 34.0 [18.0–70.0] years, 55.7% female) completed in‐person evaluation for motor and sensory impairment using the modified Total Neuropathy Score. Impairment was graded by modified Common Terminology Criteria for Adverse Events. Multivariable models estimated associations between grade ≥2 motor/sensory impairment, individual/treatment characteristics, and secondary outcomes (function by Physical Performance Test, fitness by physiologic cost index, QOL by Medical Outcomes Survey Short Form‐36 physical/mental summary scores, social attainment). Results Grade ≥2 motor or sensory impairment was more prevalent in survivors (24.1%, 95% Confidence Interval [CI] 19.8%–29.4%) than controls (2.9%, CI 1.4–4.5%). Among survivors, in multivariable models, motor impairment was associated with vinca exposure <15 mg/m2 versus none (OR 4.38, CI 1.06–18.08) and etoposide exposure >2036 mg/m2 versus none (OR 12.61, CI 2.19–72.72). Sensory impairment was associated with older age at diagnosis (OR 1.09, CI 1.01–1.16) and craniospinal irradiation versus none (OR 4.39, CI 1.68–11.50). There were lower odds of motor/sensory impairment in survivors treated in the year 2000 or later versus before 1990 (Motor: OR 0.29, CI 0.10–0.84, Sensory: OR 0.35, CI 0.13–0.96). Motor impairment was associated with impaired physical QOL (OR 2.64, CI 1.22–5.72). Conclusions In survivors of childhood CNS tumors, motor and sensory impairment is prevalent by clinical assessment, especially after exposure to etoposide, vinca, or craniospinal radiation. Treating motor impairment may improve survivors' QOL.


| INTRODUCTION
2][3][4][5] Motor and sensory impairment can impact survivors' overall health and quality of life (QOL), 2,6,7 and is amenable to rehabilitation to improve symptoms. 6urvivors of childhood CNS tumors are particularly at risk for motor and sensory impairment due to their multiple neurotoxic treatment exposures. 6,8,9These exposures include vinca alkaloid and platinum chemotherapy agents that are commonly associated with peripheral neuropathy, 6 as well as CNS insults from their primary cancer and other neurotoxic treatment modalities. 8,9However, it can be challenging to measure motor and sensory signs and symptoms that can be indicative of neuropathy in this population, and prior studies have largely relied on self-report. 10,11Better measurement of the prevalence and predictors of motor and sensory impairment in survivors of CNS tumors is needed to identify at-risk survivors who would benefit from interventions and to inform upfront treatment plans for newly diagnosed patients. 12,13he St. Jude Lifetime Cohort Study (SJLIFE) is an informative resource from which to estimate the prevalence of motor and sensory impairment in survivors of childhood CNS tumors and to evaluate individual and treatment factors associated with this outcome.The large sample of survivors with standardized in-person assessments allows for more accurate identification of motor and sensory impairment than self-report data in this complex population. 14,15Among survivors of CNS tumors participating in SJLIFE, we aimed to (1) estimate the prevalence of motor and sensory impairment (motor and sensory signs and symptoms that can be indicative of neuropathy) in survivors compared to non-first degree relative controls without a history of pediatric cancer, (2) identify individual and treatment-related factors associated with risk of motor and sensory impairment, and (3) measure associations between motor and sensory impairment and physical function, QOL, and social attainment.

| Participants
Participants were survivors of CNS tumors from SJLIFE, a retrospective cohort of childhood cancer survivors diagnosed and treated at St. Jude Children's Research Hospital between 1962 and 2012 with prospective comprehensive on-site medical evaluations.The SJLIFE Grant/Award Number: T32 CA250803 and U01 CA195547; Cancer Center Support Grant, Grant/Award Number: P30CA021765 Performance Test, fitness by physiologic cost index, QOL by Medical Outcomes Survey Short Form-36 physical/mental summary scores, social attainment).

Conclusions:
In survivors of childhood CNS tumors, motor and sensory impairment is prevalent by clinical assessment, especially after exposure to etoposide, vinca, or craniospinal radiation.Treating motor impairment may improve survivors' QOL.

K E Y W O R D S
central nervous system tumor, childhood cancer, cranial radiation, etoposide, motor impairment, peripheral neuropathy, platinum, quality of life, sensory impairment, survivorship, vinca alkaloid study design and methodology have been previously described. 14,15Participants in the current analysis had a CNS tumor treated at St. Jude, completed a functional assessment, were ≥5 years from their cancer diagnosis and ≥18 at the time of evaluation.Individuals who did not complete a campus visit or refused assessment (n = 44), or had a congenital neuromuscular disorder (n = 11) or physical or neurocognitive impairment that prevented completion of a functional assessment (n = 4), were excluded from the analysis (Figure 1).Survivors who received craniospinal irradiation (CSI) more than 5 years after their cancer diagnosis were also excluded to avoid confounding from neurotoxic exposures unrelated to their initial treatment.Of 497 CNS tumor survivors, 378 met eligibility criteria.A control group consisting of non-first-degree relatives of St. Jude patients was frequency matched to all participants in the SJLIFE cohort by age (within 5 years), sex, and race; 445 controls met eligibility criteria and were included in the analysis.The study was approved by the St. Jude Institutional Review Board, and all participants provided written informed consent.

| Primary outcomes
Motor and sensory impairment, which included motor and sensory signs and symptoms indicative of neuropathy, was identified by exercise physiologist or physical therapist evaluation using the modified Total Neuropathy Score (mTNS). 16Severity was graded using the modified version of the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 used for motor and sensory neuropathy, as previously described in SJLIFE (Table S1). 17For multivariable analyses, this outcome was dichotomized into grades 0-1 and grades ≥2 (moderate to severe impairment) to assess factors associated with motor and sensory impairment that limit activities of daily living. 18otor impairment was defined by motor symptoms and physical examination with presence of distal weakness by manual muscle examination, using the motor examination component of the mTNS. 16Additional presence of hand or foot weakness >1.5 standard deviation (SD) below community average was used to define grade ≥2 motor impairment.Hand strength was measured using a hand-held dynamometer (System 4 dynamometer; Biodex Medical Systems, Shirley, NY) 19 administered by a physical therapist/exercise physiologist trained to encourage maximum effort, and the maximum value of two sequential trials was used for analysis. 20,21Foot strength was calculated using peak torque of ankle dorsiflexion at 60/second (Biodex System 3.0, Biodex Medical Systems, Shirley, NY).The average value of the best attempt of each side was included for analysis when bilateral measures were available.
Sensory impairment was defined by sensory symptoms (including pain, numbness, or paresthesia) and physical examination with impaired pin or vibration sensibility, based on the sensory examination components of the mTNS. 16Additional presence of slowed writing speed or impaired balance in the absence of nystagmus, dysarthria, dysmetria, or dysdiadochokinesia was used to upgrade sensory impairment to grade ≥2.  25 with a score >1.5 SD below the mean of community matched controls considered impaired. 23The first item, writing time, was excluded from scoring as it was included in the definition of sensory impairment.Fitness was assessed by calculating the physiologic cost index (PCI) using the formula PCI = (maximum heart rate -resting heart rate)/gait speed, and was considered impaired if >1.5 SD above the mean of community matched controls. 25L/Social Attainment QOL was assessed using the validated Medical Outcomes Survey Short Form-36 (SF-36) version 2. 26 Physical component summary scale and mental component summary scale scores were calculated, and t-scores ≤40 were considered impaired.25

| Comorbid conditions
Chronic conditions were classified using the modified version of CTCAE 4.03 specific to childhood cancer survivors. 17,28For the current analysis, grade ≥2 chronic conditions included neurologic (hemiplegia/paraplegia, stroke, nerve root disorder, or cerebellar dysfunction), respiratory (asthma, chronic obstructive pulmonary disease, restrictive lung disease), cardiovascular (cardiomyopathy, heart failure, peripheral vascular disease), and endocrine (diabetes, obesity) conditions, as well as hearing and visual impairment. 21,29,30Survivor-report of receipt of physical therapy (PT) in the past year was also included as a covariate, as this can modify CIPN symptoms. 31

| Neurocognitive function
Neurocognitive function was included as a covariate in models examining associations between motor and sensory impairment and social attainment. 32General intelligence was measured using the Wechsler Abbreviated Scale of Intelligence (WASI). 33Additional neurocognitive domains included executive function (cognitive flexibility by Trail Making Part B, cognitive fluency by FAS word association, and working memory by digit backward) 33 and math and reading academic achievement by Woodcock-Johnson-III achievement test. 34Motor and visual/motor processing speed assessed by grooved pegboard and digitsymbol coding were included as covariates in social attainment and physical function models. 33,35All scores were converted to z-scores using standardized age/sex-based norms as previously described in this cohort. 36

| Analyses
Individual characteristics, motor impairment, sensory impairment, and physical function, QOL, and social attainment outcomes were compared between survivors and controls using chi-square or Wilcoxon rank test as appropriate.
Associations between individual characteristics, treatment exposures, disease characteristics, and grade ≥2 motor and sensory impairment were estimated using logistic or multinomial regression models.Separate regression models, adjusted for chronic conditions listed above, estimated associations between motor and sensory impairment and clinically assessed physical function, selfreported QOL, and social attainment (in survivors ages 25 years and older).The LASSO method was used to determine variables included in the final models, and logistic or multinomial regression models were re-run to estimate associations between outcomes and predictor variables. 37,38ll analyses were performed using SAS (version 9.4, Cary, North Carolina).

| Individual and treatment characteristics associated with motor and sensory impairment
Among survivors, treatment factors associated with grade ≥2 motor impairment in multivariable models included vinca alkaloid exposure ≤15 mg/m 2  Later treatment era, in 2000 or later (versus before 1990), was associated with a lower odds of motor (OR = 0.29, 95% CI 0.10-0.84)and sensory (OR = 0.35, 95% CI 0.13-0.96)impairment.Platinum exposure and cisplatin exposure alone were not associated with motor or sensory impairment.When assessing associations between treatment modality and impairment (No treatment, focal radiation, chemotherapy, CSI, or CSI and chemotherapy), treatment modality was not associated with grade ≥2 motor impairment, but the combination of CSI and chemotherapy was associated with grade ≥2 sensory impairment (OR 5.72, 95% CI 2.49-13.14)when compared with no treatment or surgery only (Table S4).

| Function, QOL, and social attainment outcomes associated with motor and sensory impairment
In multivariable models, neither motor nor sensory impairment were associated with impaired physical function or fitness; however, lower visual/motor processing (OR 0.22, 95% CI 0.14-0.37)and motor processing (OR 0.70, 95% CI 0.54-0.91)z-scores were associated with impaired physical function (Table 4).Grade ≥2 motor impairment was associated with impaired physical QOL (OR 2.64, 95% CI 1.22-5.72)but was not associated with mental QOL or social attainment.Grade ≥2 sensory impairment was not associated with QOL or social attainment (Table 5).

| DISCUSSION
Our cross-sectional study of 378 long-term survivors of childhood CNS tumors and 445 community controls quantifies the prevalence of motor and sensory impairments, using a standardized clinical assessment, in longterm survivors of childhood CNS tumors and examines their association with treatment exposures and other functional, QOL, and social attainment outcomes.In survivors of childhood CNS tumors, we demonstrated that motor or sensory impairment is prevalent in 24% of survivors by in-person evaluation and identified a novel association of etoposide and motor impairment.We also found that motor impairment is associated with impaired QOL.This study was the first to demonstrate an association between etoposide exposure and motor impairment in long-term survivors of CNS tumors, with a 12-fold increased odds of motor impairment in survivors treated with ≥2036 mg/m 2 of etoposide compared to those who were not exposed.Etoposide causes cell death by blocking an enzyme involved in DNA synthesis. 39In animal models, etoposide has led to axonal changes in large myelinated fibers consistent with neuropathy, 40 and has been associated with hind limb paralysis. 41Etoposide has also been associated with neuropathy in children receiving treatment with vincristine. 42Among 67 children treated for non-CNS cancers, etoposide exposure and vinca alkaloid exposure, compared to vinca alkaloid alone, were associated with worse neuropathy, measured by the pediatric-modified Total Neuropathy Score at 6 months post-therapy. 42We expanded on these findings by demonstrating that etoposide is associated with motor impairment in a dose-dependent fashion in survivors a median of 15 years post-diagnosis.In post-hoc analyses, we also examined whether interactions between etoposide and vinca alkaloid and etoposide and radiation exposure contributed to these findings but found no significant interactions.This finding can have important implications for clinical care since there are currently no recommendations to screen for motor or sensory impairment following etoposide exposure. 43onitoring motor function for survivors of CNS tumors following etoposide exposure should be considered as part of survivorship care so that they can receive rehabilitation services, and this association should be further explored in populations of non-CNS tumor survivors.
Another key finding of this study is the high prevalence of motor or sensory impairment in 24.1% of CNS tumor survivors and the association of motor impairment with vinca alkaloid but not platinum exposure.We found survivors exposed to vinca alkaloids at a dose up to 15 mg/ m 2 were more likely to have motor impairment than survivors who were not exposed to vinca alkaloids. 44,45 T A B L E 1 (Continued) nerve axons, 6,46,2 and have been associated with motor impairment in long-term survivors of non-CNS tumors. 2,47ur findings differ from prior studies that did not find associations of chemotherapy with motor deficits in CNS tumor survivors. 44,45In at least 5-year survivors of childhood CNS tumors from the Childhood Cancer Survivor Study, there was no association between vinca alkaloid or platinum chemotherapy and self-reported motor impairment (including weakness or difficulty moving arms or legs), but these studies were limited by self-report. 10,44 study that evaluated physical limitations in 78 survivors of childhood CNS tumors treated from 1970 to 2000 demonstrated 20.5% of survivors had loss of protective sensation, and 20.5% had hand weakness that were not associated with treatment with vinca or platinum chemotherapy. 45It is possible our findings differ from the prior studies due to the use of clinical assessments in a larger sample.We did not find an association between the higher dose of vinca alkaloid and motor impairment, but it is possible that this was due to the limited sample size in this group.Regardless, the findings highlight the need for interventions, such as rehabilitation services, 48 to minimize motor and sensory deficits in survivors of CNS tumors since nearly a quarter will experience motor or sensory impairment.
In addition to the association of vinca and etoposide exposure with motor impairment, we also found older age at diagnosis and exposure to CSI were associated with an increased risk of sensory impairment, while later treatment decade was associated with a lower risk of motor and sensory impairment in long-term survivors of CNS tumors.Radiation can cause direct nerve damage or nerve root compression from fibrosis of surrounding structures that can occur years after radiation and may explain the association of spinal radiation with sensory impairment in this study. 49Older age at time of treatment has been previously described as a risk factor for developing neuropathy during treatment in non-CNS tumor patients and may have contributed to the association of age with sensory impairment in our study. 42,50These findings suggest survivors of CNS tumors who are treated at an older age and treated with CSI may especially benefit from close monitoring for sensory deficits during survivorship care.The association of a later treatment decade with a lower risk of motor or sensory impairment likely reflects less toxic treatment protocols in later decades. 51 Grade ≥2 both 24 ( a p Values were calculated using Fisher's Exact test with missing values excluded.p values remained <0.001 when comparing grade 0-1 versus grade ≥2 impairment.
T A B L E 2 Prevalence of motor and sensory impairment in survivors and community matched controls.
of this cohort is that there were fewer survivors treated after the year 2000, which may limit the generalizability of our findings to recent survivors.However, our findings still inform care for survivors of CNS tumors currently in survivorship follow-up, and future studies should focus on confirming these findings in more recent survivors.We also found that motor and sensory deficits were clinically meaningful outcomes, highlighting the need for interventions to improve motor and sensory deficits.Grade ≥2 motor impairment was associated with patientreport of impaired physical QOL, with more than a 2-fold increased risk of impaired physical QOL among survivors with motor impairment compared with survivors without motor impairment, even when adjusting for other chronic conditions.Minimizing motor deficits may therefore be a target for to improve QOL in survivors of CNS tumors.3][54] Improvement in motor symptoms and QOL has also been observed in adults cancer survivors with neuropathy undergoing endurance and balance training. 557][58] Our findings support evaluation of these interventions in survivors of childhood CNS tumors.The lack of association between motor and sensory impairment and impaired physical function was unexpected.This finding differs from other studies that found associations of motor and sensory impairments with daily function in survivors of non-CNS tumors. 7,25Among 25,583 survivors of childhood cancer from the Childhood Cancer Survivor Study, neuromuscular dysfunction was associated with impaired activities of daily living. 7Among 206 survivors of extremity sarcoma from SJLIFE, motor neuropathy was associated with impaired fitness and limited activities of daily living. 25We found that poorer visual/motor and motor processing skills were associated with impaired physical function, suggesting central motor processes were larger contributors to physical function than the motor signs and symptoms measured by the mTNS. 59,60This is similar to a study of 365 survivors of acute lymphoblastic leukemia from SJLIFE in which visual-motor processing speed, but not peripheral sensory impairment, was associated with impaired balance. 61Our findings suggest that motor and sensory signs and symptoms, as well as central motor processing, impact QOL and physical function in survivors of CNS tumors, and therefore interventions to improve motor and sensory impairment are needed.
The results of our study should be interpreted in the context of potential limitations in addition to those already mentioned.Survivors were treated at a single institution, and results may not be generalizable to all populations of childhood CNS tumor survivors.3][64] However, this sample allowed for indepth clinical evaluations in a large, diverse population of survivors of CNS tumors, 65 that are not available with other datasets.We could also only include survivors who were able to complete an in-person clinical assessment in this study, which may have limited inclusion of the most impaired survivors.Only four survivors who returned for an assessment were unable to complete their evaluation due to functional limitation, so we do not believe this impacted our findings.Furthermore, survivors who returned for assessments had similar markers of performance status including employment status, independent living status, and physical QOL, to survivors who did not return for assessments, suggesting this was a representative sample.Another potential limitation is that this study included survivors at least 5 years from their cancer diagnosis and does not reflect the prevalence of motor and sensory    Motor processing refers to performance on grooved pegboard test, and visual motor processing refers to performance on digit-symbol coding test.
impairment among those who did not survive 5 years from diagnosis.This may have overestimated or underestimated the true prevalence of this outcome.However, these findings still inform care for an important, growing population of long-term survivors who survive 5 years.Finally, while we tried to define motor and sensory impairment as signs and symptoms indicative of neuropathy by using a validated instrument administered by an inperson trained exercise physiologist or physical therapist, it is possible both peripheral and central causes contributed to impairment.Regardless of the etiology, we were still able to demonstrate the high prevalence of motor and sensory impairment in survivors of CNS tumors and its association with impactful daily outcomes that will inform care for this group.

| CONCLUSIONS
Approximately one quarter of survivors of childhood CNS tumors had grade ≥2 motor or sensory impairment on exam, which was associated with impaired QOL.Etoposide and vinca alkaloid exposure were associated with motor impairment, while older age and CSI were associated with sensory impairment.Survivors of CNS tumors should be monitored for motor and sensory impairment, and interventions that target motor impairment may be warranted to improve their QOL.

T A B L E 1
Characteristics of survivors and age-, sex-, race-matched community controls.

T A B L E 5
Association of grade ≥2 motor and sensory impairment and sensory impairment with QOL and role attainment outcomes in survivors in multivariable models.a Abbreviation: QOL, quality of life.a LASSO model selection was used to determine variables included in the final model.Motor impairment was not selected for employment, independent living, or education outcomes and was included to estimate associations.Sensory impairment was not selected for any outcomes but was included to estimate associations.bImpaired mental and physical QOL defined as t-score ≤ 40 on mental and physical component summary scales of the Medical Outcomes Survey Short Form-36.

2.3 | Individual and disease characteristics
14036 mg/m 2 ) history of radiation (none, cranial only, or CSI), CSI by dose (0 cGy, 0 to ≤3295 cGy, and >3295 cGy), maximum radiation dose to the posterior fossa (by tertile of exposure), tumor location (supratentorial, posterior fossa, or spinal cord),27type of surgery (gross or near total resection, partial resection, or no surgery/biopsy only), history of hydrocephalus,14age at diagnosis, and treatment era(before 1990, 1990-1999,  2000 and later).Treatment factors were also grouped by modality (no treatment or surgery only, focal radiation, chemotherapy [with or without focal radiation], CSI, CSI with chemotherapy).The cut-point for vinca alkaloid, platinum, etoposide, and CSI dose was based on examination of receiver operating curves with the outcome grade ≥2 motor impairment.
Vinca alkaloids can cause both motor and sensory impairment through inhibition of microtubule function in peripheral a p Value is describing comparison between survivors and controls.b p Value is describing comparison between survivor participants and non-participants.c Independent living = lives with spouse, alone, or roommate, Dependent living = Lives with parent, siblings, or other non-child relative.d Cumulative dose of cisplatin and carboplatin.e Each treatment modality included participants who also received surgery.
A limitation Treatment and disease characteristics associated with grade ≥2 motor and sensory impairment in multivariable models.aAgeat diagnosis, treatment era, platinum dose, and etoposide dose were not selected for motor or sensory neuropathy models, but were forced in to estimate associations.Vinca alkaloid was included as dichotomous variable in sensory model and categorized by cumulative exposure dose in motor model based on examination of distribution and examination of receiver operating characteristic curves.Vinca alkaloid dose was not selected for motor impairment model, but was forced in to estimate associations.
T A B L E 3 a LASSO model selection was used to determine variables included in the final model.bc Blank cell indicates variable not selected for this model.de Association of grade ≥2 motor and sensory impairment with physical function outcomes in survivors in multivariable models.a Model selection was performed using the LASSO method to determine variables included in the final model.For impaired physical function motor and sensory impairment were not selected for the model but were included to estimate associations.Motor processing refers to performance on grooved pegboard test, and visual motor processing refers to performance on digit-symbol coding test.
T A B L E 4 Note: Bold value indicates p-value <0.05.Abbreviation: IQ; intelligence quotient.a b Impaired physical function measured by Physical Performance Test with impairment defined as a score >1.5 standard deviations below the community average.c Impaired fitness measured by Physiologic Cost Index with impairment defined as a score >1.5 standard deviations above the community average.d Blank cell indicates variable not selected for given outcome in adjusted model.e